Combination therapy with oral antiviral and anti-inflammatory drugs improves the efficacy of delayed treatment in a COVID-19 hamster model.

Background: Pulmonary infection with SARS-CoV-2 stimulates host immune responses and can also result in the progression of dysregulated and critical inflammation. Throughout the pandemic, the management and treatment of COVID-19 has been continuously updated with a range of antiviral drugs and immunomodulators. Monotherapy with oral antivirals has proven to be effective in the treatment of COVID-19. However, treatment should be initiated in the early stages of infection to ensure beneficial therapeutic outcomes, and there is still room for further consideration on therapeutic strategies using antivirals.
Methods: We studied the therapeutic effects of monotherapy with the oral antiviral ensitrelvir or the anti-inflammatory corticosteroid methylprednisolone and combination therapy with ensitrelvir and methylprednisolone in a delayed dosing model of hamsters infected with SARS-CoV-2.
Findings: Combination therapy with ensitrelvir and methylprednisolone improved respiratory conditions and reduced the development of pneumonia in hamsters even when the treatment was started after 2 days post-infection. The combination therapy led to a differential histological and transcriptomic pattern in comparison to either of the monotherapies, with reduced lung damage and down-regulation of expression of genes involved in the inflammatory response. Furthermore, we found that the combination treatment is effective in case of infection with either the highly pathogenic delta or circulating omicron variants.
Interpretation: Our results demonstrate the advantage of combination therapy with antiviral and corticosteroid drugs in COVID-19 treatment from the perspective of lung pathology and host inflammatory responses.
Funding: Funding bodies are described in the Acknowledgments section.
Competing Interests: Declaration of interests SK, HN and ST owns stocks in Shionogi & Co., Ltd. KM, YO and HS are involved in joint research contract between Shionogi & Co., Ltd., and Hokkaido University. MS has received fees for speaker bureaus from Shionogi & Co., Ltd. MS, HN, ST and HS are inventors on patent application numbers PCT/JP2022/035803 (MS, HN, ST and HS), PCT/JP2022/6495 and PCT/JP2022/6496 (MS) submitted by Shionogi & Co., Ltd., and Hokkaido University that covers ETV. SI has received grants from Japan Society for the Promotion of Science. TS has received grants from Japan Society for the Promotion of Science and Japan Agency for Medical Research and Development. HS has received grants from Japan Agency for Medical Research and Development. The remaining authors have no potential competing interests to declare.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)